Focal segmental glomerulosclerosis (FSGS) is the most common glomerular lesion leading to ESRD in Children. Approximately one-fifth of the steroid resistant patients with FSGS (SRFSGS) will respond to cyclospodne (CS). Those unresponsive patients will progress over a variable time interval to ESRD. The rate of progression is particularly severe in African-American and Hispanic children. To date no controlled trial with novel immunomodulatory agent(s) has demonstrated efficacy inducing a complete remission in SRFSGS patients who fail to respond to CS. The Specific Aims of this proposal are to compare two regimens: (a) low-dose CS and sirolimus, and (b) intravenous methylprednisolone and cyclophosphamide in patients with SRFSGS who do not respond with a complete remission to a 16 week course of CS and low-dose prednisone in order to determine which regimen is more efficacious with fewer side-effects. An additional Specific Aim will attempt to predict progression in patients with SRFSGS by Sirius Red staining and by detecting fibrogenic cytokines in renal biopsy tissue at enrollment and 18 months after randomization. Additionally, 125I-iothalamate will be compared with Cystatin C as a measure of glomerular filtration rate (GFR) in order to determine if the latter is an acceptable "gold standard" for serial measurement of GFR in patients with SRFSGS.